A new saccharide sensor based on a tetrathiafulvalene - Anthracene dyad with a boronic acid group

Article abstract of DOI:10.1021/jo050682e

A new saccharide sensor based on a tetrathiafulvalene-anthracene dyad with a boronic acid group was designed and synthesized. Our study employed the tetrathiafulvalene (TTF) unit as the electron-rich group in the saccharide sensor instead of an amine grou

Full text of DOI:10.1021/jo050682e

SCHEME 1
A New Saccharide Sensor Based on a
Tetrathiafulvalene-Anthracene Dyad with
a Boronic Acid Group
Zhuo Wang,†,‡ Deqing Zhang,*,† and Daoben Zhu*,†
Center for Molecular Sciences, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China, and
Graduate School, Chinese Academy of Sciences,
Beijing 100080, China
dqzhang@iccas.ac.cn
Received April 6, 2005
kai and co-workers have studied extensively the saccha-
ride sensors based on the PET mechanism containing
three components: a fluorophore, an amine, and a bor-
onic group (Scheme 1).5,6a,b As shown in Scheme 1, the
nitrogen-boron interaction modulates the PET process
and leads to fluorescence change before and after the
bonding of the boronic acid group with saccharides. The
interaction of the boronic acid and amine groups also
confers a working pH of these saccharide sensors devel-
oped by Shinkai et al. close to physiological pH. To our
best knowledge, however, only the amine group was used
as the electron-rich center to design Shinkai’s saccharide
sensors.
Tetrathiafulvalene (TTF) derivatives, widely used as
components of organic conductors and superconductors,
A new saccharide sensor based on a tetrathiafulvalene-
anthracene dyad with a boronic acid group was designed and
synthesized. Our study employed the tetrathiafulvalene
(TTF) unit as the electron-rich group in the saccharide
sensor instead of an amine group, and this new sensor
detects fructose with good selectivity.
7
are good electron donors. In recent years, TTF deriva-
tives have been employed to construct molecular shuttles8
and redox fluorescence switches.9 With this in mind, we
studied the possible substitution of the amine group of
(5) See for reviews: (a) James, T. D.; Sandanayake, K. R. A. S.;
Shinkai, S. Angew, Chem., Int. Ed. 1996, 35, 1910. (b) James, T. D.;
Linnane, P.; Shinkai, S. Chem. Commun. 1996, 281. Other saccharide
sensors operated by multiple hydrogen bonds also have been re-
ported: (c) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. Engl.
1999, 38, 2978 and further references therein. (d) Fang, J.; Selvi, S.;
Liao, J.; Slanina, Z.; Chen, C.; Chou, P. J. Am. Chem. Soc. 2004, 126,
3559.
(6) See for examples: (a) Nagase, T.; Nakata, E.; Shinkai, S.;
Hamachi, I. Chem. Eur. J. 2003, 9, 3660. (b) Nakata, E.; Nagase, T.;
Shinkai, S.; Hamachi, I. J. Am. Chem. Soc. 2004, 126, 490. (c) Arimori,
S.; Consiglio, G. A.; Phillips, M. D.; James, T. D. Tetrahedron Lett.
2003, 44, 4789. (d) Arimori, S.; Phillips, M. D.; James, T. D. Tetrahe-
dron Lett. 2004, 45, 1539. (e) Arimori, S.; Bell, M. L.; Oh, C. S.; James,
T. D. Org. Lett. 2002, 4, 4249. (f) Yang, W.; Yan, J.; Fang, H.; Wang,
B. Chem. Commun. 2003, 792. (g) Zhao, J.; Davidson, M. G.; Mahon,
M. F.; Kociok-kn˜hn, G.; Jams, T. D. J. Am. Chem. Soc. 2004, 126,
16179. (h) Gao, X.; Zhang, Y.; Wang, B. Org. Lett. 2003, 5, 4615. (i)
DiCesare, N.; Lakowicz, J. R. J. Phys. Chem. A 2001, 6834. (j)
DiCesare, N.; Lakowicz, J. R. Tetrahedron Lett. 2002, 43, 2615. (k)
Arimori, S.; Bosch, L. I.; Ward, C. J.; James, T. D. Tetrahedron Lett.
2001, 42, 4553. (l) Yang, W.; Yan, J.; Springsteen, G.; Deeter, S.; Wang,
B. Bioorg. Med. Chem. Lett. 2003, 13, 1019.
Saccharides play significant roles in biological pro-
cesses. Development of new saccharide sensors is highly
desired to understand cellular activities and diagnose
diseases.1 The boronic acid group can form cyclic esters
with saccharides reversibly, and molecules featuring
boronic acid groups have been investigated for saccharide
recognition through various signal transduction mecha-
nisms, such as CD,2 absorption,3 electrochemical prop-
erty,4 and fluorescence.5 Two mechanisms have been
employed to design effective saccharide sensors: the
photoinduced electron-transfer mechanism (PET)6a-g and
the internal charge-transfer mechanism (ICT).6h-l Shin-
† Center for Molecular Sciences, Institute of Chemistry.
‡ Graduate School.
(1) Henning, T. P.; Cunningham, D. C. In Commercial Biosensors:
Applications to Clinical, Bioprocess, and Environmental Samples;
Ramsay, G., Ed.; Wiley: New York, 1998.
(2) See for examples: (a) Tsukagoshi, K.; Shinkai, S. J. Org. Chem.
1991, 56, 4089. (b) Sandanayake, K. R. A. S.; James, T. D.; Shinkai,
S. Pure Appl. Chem. 1996, 68, 1207. (c) Sugasaki, A.; Sugiyasu, K.;
Ikeda, M.; Takeuchi, M.; Shinkai, S. J. Am. Chem. Soc. 2001, 123,
10239. (d) Takeuchi, M.; Mizuno, T.; Shinkai, S.; Shirakami, S.; Itoh,
T. Tetrahedron: Asymmetry 2000, 11, 3311. (e) Zhao, J.; Fyles, T. M.;
James, T. D. Angew. Chem., Int. Ed. 2004, 43, 3461 and references
therein.
(3) See for examples: (a) Takeuchi, M.; Kijima, H.; Hamachi, I.;
Shinkai, S. Bull. Chem. Soc. Jpn. 1997, 70, 699. (b) Shinmori, H.;
Takeuchi, M.; Shinkai, S. J. Chem. Soc., Perkin Trans. 2 1998, 847.
(c) Ward, C. J.; Patel, P.; James, T. D. J. Chem. Soc., Perkin Trans. 1
2002, 462. (d) Camara, J. N.; Suri, J. T.; Cappuccio, F. E.; Wessling,
R. A.; Singaram, B. Tetrahedron Lett. 2002, 43, 1139.
(4) See for examples: (a) Ori, A.; Shinkai, S. J. Chem. Soc., Chem.
Commun. 1995, 1771. (b) Arimori, S.; Ushiroda, S.; Peter, L. M.;
Jenkins, A. T. A.; James, T. D. Chem. Commun. 2002, 2368.
(7) Williams, J. M.; Ferraro, J. R.; Thorn, R. J.; Carlson, K. D.;
Geiser, U.; Wang, H. H.; Kini, A. M.; Wangbo, M.-H. Organic
Superconductors (Including Fullerenes); Prentice Hall: Englewood
Cliffs, NJ, 1992.
(8) See for examples: (a) Pease, A. R.; Jeppesen, J. O.; Stoddart, J.
F.; Luo, Y.; Collier, C. P.; Heath, J. R. Acc. Chem. Res. 2001, 34, 433.
(b) Jeppesen, J. O.; Perkins, J.; Becher, J.; Stoddart, J. F. Angew.
Chem., Int. Ed. 2001, 40, 1216. (c) Collier, C. P.; Jeppesen, J. O.; Luo,
Y.; Perkins, J.; Wong, E. W.; Health, J. R.; Stoddart, J. F. J. Am. Chem.
Soc. 2001, 123, 12632.
(9) (a) Li, H.; Jeppesen, J. O.; Levillain, E.; Becher, J. Chem.
Commun. 2003, 846. (b) Zhang, G.; Zhang, D.; Guo, X.; Zhu, D. Org.
Lett. 2004, 6, 1209. (c) Bryce, M. R. Adv. Mater. 1999, 11, 11 and
references therein. (d) Segura, J. L.; Mart´ın, N. Angew. Chem., Int.
Ed. 2001, 40, 1372 and references therein. (e) Farren, C.; Christensen,
C. A.; FitzGerald, S.; Bryce, M. R.; Beeby, A. J. Org. Chem. 2002, 67,
9130.
10.1021/jo050682e CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/08/2005
J. Org. Chem. 2005, 70, 5729-5732
5729

SCHEME 2
FIGURE 1. Fluorescence spectra of dyad 1 (5.0 × 10-5 M)
with different concentrations of fructose (0-50 mM) at pH 7.3
adjusted by 0.033 M phosphate buffer in THF/H2O (1:1, v/v);
the excitation wavelength is 370 nm. The inset shows the
relative fluorescence intensity profile of 1 and 2 vs fructose
concentration.
Figure 1 shows the fluorescence spectra of dyad 1 in
the presence of different concentrations of fructose at pH
7.3 in THF/H2O (1:1, v/v). Before reaction with fructose,
dyad 1 shows rather weak fluorescence. As for the
anthracene-TTF-anthracene triad reported by us pre-
viously,9b the weak fluorescence of 1 could be attributed
to the PET between the excited anthracene and TTF
units.14 The quenching effect of the boronic acid group,15
which is a weak electron acceptor, may also contribute
to the weak fluorescence of 1. But, the TTF unit shows
strong electron donating ability, and thus the weak fluor-
escence of 1 should be mainly due to the PET between
the excited anthracene and TTF units. After addition of
fructose, the fluorescence of the solution of dayd 1 was
enhanced. A 5-fold fluorescence enhancement was ob-
served when the concentration of fructose reached 50 mM
(Figure 1). Compared to other fructose sensors reported
previously under similar conditions, such fluorescence
response of the solution of dyad 1 to fructose is relatively
larger.5
Shinkai’s saccharide sensors with the TTF group for
development of a new saccharide sensor as shown in our
TTF-anthracene dyad 1 (Scheme 2). Herein we describe
the synthesis and fluorescent spectral studies of 1 in the
presence of saccharides. The results demonstrate that
dyad 1 is a new saccharide sensor.
Synthesis of dyad 1 started from compound 3 (Scheme
2).10 Selective deprotection of one of the 2-cyanoethyl
groups in 3 with CsOH‚H2O and further reaction with
9-(2-bromoethoxyl)anthracene afforded compound 4, from
which compound 5 was yielded by similar procedures
with 1,3-dibromopropane. Reaction of 5 and 2-(4-carboxy-
phenyl)-5, 5-dimethyl-1,3,2-dioxaborinane11 in the pres-
ence of anhydrous potassium carbonate led to compound
6. Dyad 1 was obtained by hydrolysis of 6 with hydro-
chloric acid solution (1.2 M) in a total 14% yield after
purification with column chromatography.12 The two
isomers (cis and trans) of dyad 1 were not separable with
column chromatography.13 But, that would not affect the
following fluorescent studies of dyad 1.
Under identical conditions, the fluorescence spectra of
dyad 1 in the presence of other saccharides such as
(13) The ratio of the cis/trans isomers of dyad 1 should be 1:1 since
that of the cis/trans isomers of the starting compound 3 is 1:1
(compound 3 was synthesized from 4-(2-cyanoethylthio)-1,3-dithiole-
2-one in the presence of trialkyl phosphite). We could not determine
the binding constants of the cis/trans isomers of 1 with saccharides as
we could not separate them with column chromatography. But, it
cannot be expected that there is a large difference between the cis/
trans isomers of 1 in terms of binding saccharides. This is because it
is the boronic acid group that reacts with saccharides and the influence
of the anthracene group on the binding should be rather limited since
the boronic acid and anthracene groups are separated by a relatively
long distance.
(14) The first oxidation potential of dyad 1 was measured to be 0.54
V (vs Ag/AgCl) in THF, which was due to the oxidation of the TTF
unit into the corresponding radical cation. The second oxidation
potential (for TTF.+ to TTF2+) and the irreversible oxidation peak due
to the oxidation of the anthracene unit were measured to be 0.90 and
1.70 V, respectively. Besides, an irreversible reduction wave (-1.89
V) was observed for dyad 1, and this was ascribed to the reduction of
the anthracene unit. Accordingly, the free energy (∆GPET) for the PET
from the TTF unit to the anthracene unit was estimated to be -0.83
eV with the Rehm-Weller equation: ∆GPET ) -E(ex.) - E(red.) +
E(ox.) - e2/ꢀr, with E(ox.) ) 0.54 eV, E(red.) ) -1.89 eV, λ(ex.) ) 370
nm, and e2/ꢀr ) -0.1 eV. See: (a) Rehm, D.; Weller, A. Isr. J. Chem.
1970, 8, 259. (b) Grabowski, Z. R.; Dobkowski, J. Pure Appl. Chem.
1983, 55, 245.
(10) (a) Jia, C.; Zhang, D.; Xu, W.; Zhu, D. Org. Lett. 2001, 3, 1941.
(b) Jia, C.-Y.; Zhang, D.-Q.; Guo, X.-F.; Wan, S.-H.; Xu, W.; Zhu, D.-B.
Synthesis 2002, 15, 2177.
(11) Matsubara, H.; Seto, K.; Tahara, T.; Takahashi, S. Bull. Chem.
Soc. Jpn. 1989, 62, 3896.
(12) Characterization data for dyad 1: 1H NMR (400 MHz, CDCl3,
see Supporting Information) δ 2.12 (m, 2H), 2.93 (m, 2H), 3.36 (m, 2H),
4.35 (m, 4H), 4.63 (s, 1H), 4.66 (s, 1H), 6.41 (s, 1H), 6.48 (s, 1H), 7.48
(m, 4H), 7.79-8.25 (m, 9H); 13C NMR (100.6 MHz, CDCl3) δ 35.88,
63.08, 63.16, 73.33, 73.38, 122.14, 122.64, 122.76, 123.11, 124.47,
124.51, 124.55, 125.41, 125.49, 128.45, 128.82, 128.88, 132.24, 132.28,
132.32, 133.56, 133.44, 150.20, 166.31; ESI-MS (M + 1)+, 695.2; HRMS
Anal. Calcd for (C32H27BO5S6‚CH3OH + Na)+ 750.0532, found 750.0549;
FT-IR (KBr, cm-1) 3431, 3057, 2924, 1714, 1625, 1341, 1273, 1094,
881, 844.
(15) Tong, A.-J.; Yamauchi, A.; Hayashita, T.; Zhang, Z.-Y.; Smith,
B. D.; Teramae, N. Anal. Chem. 2001, 73, 1530.
5730 J. Org. Chem., Vol. 70, No. 14, 2005

FIGURE 2. Fluorescence intensity change of dyad 1 (5.0 ×
10-5 M) in 0.033 M phosphate buffer at pH 7.3 as a function
of sugar concentration (fructose, gluctose, galactose, mannose);
I0 is the fluorescence intensity of the solution of dyad 1 in the
absence of sugar; the solvent is THF/H2O (1:1, v/v), and the
excitation wavelength is 370 nm.
FIGURE 3. Relative fluorescence intensity profile vs pH for
dyad 1 and 2 (5.0 × 10-5 M) in the presence of fructose (25
mM) in THF/H2O (1:1, v/v) adjusted by 0.033 M phosphate
buffer; IpH5.2 is the fluorescence intensity of 1 or 2 at pH 5.2;
the excitation wavelength is 370 nm.
cence spectra of 2 in the presence of fructose were also
measured in solutions at different pH values. The
fluorescence intensity of 2 containing fructose (25 mM)
was enhanced by increasing the pH values of the solution,
which is different from that observed for dyad 1 (Figure
3). According to a previous report,15 the observed fluo-
rescence enhancement for 2 should be due to the trans-
formation of the boronic acid group into the boronate
anion (losing electron accepting ability).
TABLE 1. Association Constants (Ka) and Fluorescence
Intensity Changes (I/I0) of Dyad 1 with Different Sugars
sugar
Ka
I/I0
fructose
mannose
glucose
115 ( 2 (r2 ) 0.99)
81 ( 8 (r2 ) 0.98)
70 ( 7 (r2 ) 0.98)
66 ( 7 (r2 ) 0.98)
5.01
1.82
1.40
1.35
galactose
mannose, glucose, and galactose were also investigated.
Figure 2 shows the variation of the fluorescence intensity
of dyad 1 with the concentration of fructose, mannose,
glucose, and galactose. After the reaction of dyad 1 with
mannose or glucose or galactose, the fluorescence of the
solution of 1 does increase. But, compared to fructose,
the degree of the fluorescence enhancement is relatively
small for mannose, glucose, and galactose. By fitting the
data shown in Figure 2, the association constants (Ka) of
dyad 1 with fructose, mannose, glucose, and galactose
were evaluated and the data are listed in Table 1.16 These
association constant data also show that dyad 1 binds
more strongly with fructose.
The fluorescence response of dyad 1 to saccharides was
also studied at different pH values. As an example,
Figure 3 displays the relationship between fluorescence
and pH of dyad 1 in solutions containing fructose (25
mM). Clearly, the fluorescence intensity increases very
slightly when the pH of the solution is below 6.0, and it
reaches maximum around pH 7.3, which is in the range
of physiological pH. Similar phenomena were also seen
for mannose, glucose, and galactose.
Two conclusions can be drawn from the different
behaviors of dyad 1 and 2 in terms of fluorescence
increase upon reaction with saccharides: (1) the observed
fluorescence enhancement for dyad 1 cannot be solely
due to the transformation of the boronic acid into the
boronate ion since dyad 1 shows a larger fluorescence
increase compared with 2 under identical conditions and
(2) the TTF unit in dyad 1 plays an important role in
the fluorescence enhancement upon the binding of the
boronic acid group with saccharides. The fluorescence
enhancement observed for dyad 1 upon reaction with
saccharides can be understood as follows: upon reaction
with saccharides, the boronic acid group was converted
to the boronate under the present conditions. According
to previous studies,5 the boronate is a stronger Lewis acid
(i.e., stronger electron acceptor) than the corresponding
boronic acid. As a result, the PET between the TTF unit
and boronate would compete with that between the TTF
and anthracene units of dyad 1, which in turn would be
prohibited to some extent, leading to the fluorescence
enhancement of dyad 1. Accordingly, we suppose that the
mechanism of dyad 1 sensing saccharides is similar to
that of Shinkai’s saccharide sensors (Scheme 1).
In summary, a new TTF-anthracene dyad 1 with a
boronic acid group was synthesized, and fluorescent
spectral studies show that dyad 1 is a good saccharide
(at least for fructose) sensor. Comparative studies with
compound 2 indicate that the TTF group plays an
important role for the observed fluorescence enhance-
ment for dyad 1 after reaction with saccharides. The
present studies suggest that the amine group in Shinkai’s
saccharide sensors can be replaced with other electron-
rich centers such as the TTF group, extending the gamut
of Shinkai’s saccharide sensors. Moreover, the nature of
the TTF/anthracene and TTF/boronic spacers may affect
To study the role of the TTF unit on the fluorescence
enhancement upon binding with saccharides, studies of
the reference compound 2 (Scheme 2) under identical
conditions were carried out. The inset of Figure 1 shows
the fluorescence alteration of 2 upon reaction with
fructose together with that of 1 for comparison. Obvi-
ously, compared with dyad 1 only slight fluorescence
enhancement was observed for 2. Besides, the fluores-
(16) The K values shown in Table 1 were calculated from the plots
of relative fluorescence intensity versus saccharide concentration by
using the following equation: IF ) (IFmin + IFmax K[guest])/(1 +
K[guest]). The standard errors obtained from the best fitting were also
provided.
J. Org. Chem, Vol. 70, No. 14, 2005 5731

the sensitivity of dyad 1 to saccharides, adding new
thoughts for designing effective saccharide sensors. Fur-
ther investigations along this vein are in progress.
anonymous reviewers for the critical comments which
enabled us to greatly improve the manuscript.
Supporting Information Available: Synthesis and char-
acterization of compounds 1, 2, 4, 5, 6, and 7; fluorescence
spectra of 2 in the presence of fructose; 1H NMR spectra of
dyad 1 and 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. The present research was finan-
cially supported by NSFC, Chinese Academy of Sciences,
and State Key Basic Research Program (G2000077505).
D.-Q.Z. thanks the National Science Fund for Distin-
guished Young Scholars. The authors also thank the
JO050682E
5732 J. Org. Chem., Vol. 70, No. 14, 2005